Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.

Motivation: Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia. Results: We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified. Availability and implementation: Datasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/. Supplementary information: Supplementary data are available at Bioinformatics online.

Agglomerative joint clustering of metabolic data with spike at zero: A Bayesian perspective.

In many biological applications, for example high-dimensional metabolic data, the measurements consist of several continuous measurements of subjects or tissues over multiple attributes or metabolites. Measurement values are put in a matrix with subjects in rows and attributes in columns. The analysis of such data requires grouping subjects and attributes to provide a primitive guide toward data modeling. A common approach is to group subjects and attributes separately, and construct a two-dimensional dendrogram tree, once on rows and then on columns. This simple approach provides a grouping visualization through two separate trees, which is difficult to interpret jointly. When a joint grouping of rows and columns is of interest, it is more natural to partition the data matrix directly. Our suggestion is to build a dendrogram on the matrix directly, thus generalizing the two-dimensional dendrogram tree to a three-dimensional forest. The contribution of this research to the statistical analysis of metabolic data is threefold. First, a novel spike-and-slab model in various hierarchies is proposed to identify discriminant rows and columns. Second, an agglomerative approach is suggested to organize joint clusters. Third, a new visualization tool is invented to demonstrate the collection of joint clusters. The new method is motivated over gas chromatography mass spectrometry (GCMS) metabolic data, but can be applied to other continuous measurements with spike at zero property.

Impact of Occupational Exposure to Chemicals in Life Cycle Assessment: A Novel Characterization Model Based on Measured Concentrations and Labor Hours.

According to Lim et al., based on World Health Organization (WHO) data, hazardous chemicals in the workplace are responsible for over 370,000 premature deaths annually. Despite these high figures, life cycle impact assessment (LCIA) does not yet include a fully operational method to consider occupational impacts in its scope over the entire supply chain. This paper describes a novel approach to account for occupational exposure to chemicals by inhalation in LCA. It combines labor statistics and measured occupational concentrations of chemicals from the OSHA database to calculate operational LCIA characterization factors (i.e., intakes per hour worked and impact intensities for 19,069 organic chemical/sector combinations with confidence intervals across the entire U.S. manufacturing industry). For the seven chemicals that most contribute to the global impact, measured workplace concentrations range between 5 × 10(-4) and 3 × 10(3) mg/m(3). Carcinogenic impacts range over 4 orders of magnitude, from 1.3 × 10(-8) and up to 3.4 × 10(-4) DALY per blue-collar worker labor hour. The innovative approach set out in this paper assesses health impacts from occupational exposure to chemicals with population exposure to outdoor emissions, making it possible to integrate occupational exposure within LCIA. It broadens the LCIA scope to analyze hotspots and avoid impact shifting.

Testing multiple variance components in linear mixed-effects models.

Testing zero variance components is one of the most challenging problems in the context of linear mixed-effects (LME) models. The usual asymptotic chi-square distribution of the likelihood ratio and score statistics under this null hypothesis is incorrect because the null is on the boundary of the parameter space. During the last two decades many tests have been proposed to overcome this difficulty, but these tests cannot be easily applied for testing multiple variance components, especially for testing a subset of them. We instead introduce a simple test statistic based on the variance least square estimator of variance components. With this comes a permutation procedure to approximate its finite sample distribution. The proposed test covers testing multiple variance components and any subset of them in LME models. Interestingly, our method does not depend on the distribution of the random effects and errors except for their mean and variance. We show, via simulations, that the proposed test has good operating characteristics with respect to Type I error and power. We conclude with an application of our process using real data from a study of the association of hyperglycemia and relative hyperinsulinemia.

Rapid classification of phenotypic mutants of Arabidopsis via metabolite fingerprinting.

We evaluated the application of gas chromatography-mass spectrometry metabolic fingerprinting to classify forward genetic mutants with similar phenotypes. Mutations affecting distinct metabolic or signaling pathways can result in common phenotypic traits that are used to identify mutants in genetic screens. Measurement of a broad range of metabolites provides information about the underlying processes affected in such mutants. Metabolite profiles of Arabidopsis (Arabidopsis thaliana) mutants defective in starch metabolism and uncharacterized mutants displaying a starch-excess phenotype were compared. Each genotype displayed a unique fingerprint. Statistical methods grouped the mutants robustly into distinct classes. Determining the genes mutated in three uncharacterized mutants confirmed that those clustering with known mutants were genuinely defective in starch metabolism. A mutant that clustered away from the known mutants was defective in the circadian clock and had a pleiotropic starch-excess phenotype. These results indicate that metabolic fingerprinting is a powerful tool that can rapidly classify forward genetic mutants and streamline the process of gene discovery.